It is unclear what factors make certain individuals vulnerable to episodes of major depression, a chronic, severe illness which levies a crippling toll on the individual, their family and eventually society. My long term objective is to understand the biological vulnerability factors that confer trait vulnerability to recurrent depressive disorder. With this long term objective, I have gathered data on individuals vulnerable to depression at the University of Oxford, UK, using a combination of positron emission tomography (PET), magnetic resonance spectroscopy (MRS) and neuroendocrine assays. Using these measures I have elicited abnormalities in systems considered fundamental to the pathophysiology to depression including the serotonin (5-HT) system, the hypothalamic pituitary adrenal axis (HPA) and cortical gamma amino butyric acid (GABA). However, I believe that the critical factor which makes certain individuals vulnerable to depression is not an isolated abnormality in an individual biological system but is a maladaptive interaction of these systems. My preliminary data show that there is an enduring deficit in cortical GABA levels measured with magnetic resonance spectroscopy (MRS), which is independent of mood state and prior treatment, in individuals who have experienced recurrent depressive illness. I have also demonstrated that healthy control individuals with an s allele of the 5-HT transporter polymorphism (5-HTTPRL) have lower cortical GABA levels. Preliminary data also suggests that individuals with the s allele of the 5-HTTPRL experience are more likely to experience a relapse of depressive symptoms following tryptophan depletion. I propose to study the interactions of these critical systems. The specific aims for this proposal are 1. To study whether the 5-HT system is a critical mediator of the GABA deficits associated with vulnerability to depression. 2. To test a molecular model of vulnerability to depression. Design: I will perform two experiments. 1.1 propose to study the effect of acute tryptophan depletion on cortical GABA levels measured by proton MRS in fully recovered, euthymic, medication free subjects with a history of recurrent major depressive disorder in a placebo controlled, balanced order, double blind design. Subjects within each group will also be studied to determine the effect of polymorphisms of the 5-HTTPRL on cortical GABA. 2.1 will also follow up the cohort of fully recovered, euthymic, medication free subjects with a history of recurrent major depressive disorder in experiment 1 ,'to determine whether subjects who relapse over 2 years have lower cortical GABA compared with subjects who do not relapse. Relevance: Depression is a common and severe illness which is thought to occur as a result of a dysfunction of brain chemicals. Using sophisticated brain imaging techniques and genetic analysis, this project will study the interaction of two main brain chemicals implicated in the causation of depression.